Portal de Periódicos da CAPES

A map and new directions for the (pro)renin receptor in the brain : focus on “A role of the (pro)renin receptor in neuronal cell differentiation”

2009; American Physiological Society; Volume: 297; Issue: 2 Linguagem: Inglês

10.1152/ajpregu.00287.2009

1522-1490

Eric Lazartigues,

Apelin-related biomedical research

EDITORIAL FOCUSA map and new directions for the (pro)renin receptor in the brain: focus on "A role of the (pro)renin receptor in neuronal cell differentiation"Eric LazartiguesEric LazartiguesPublished Online:01 Aug 2009https://doi.org/10.1152/ajpregu.00287.2009This is the final version - click for previous versionMoreSectionsPDF (311 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat over the last few decades, the renin-angiotensin system (RAS) has seen the discovery of several new members, both in the periphery and in the central nervous system (CNS), including substrates, enzymes, and receptors, and one may wonder why textbooks are still teaching an oversimplified and outdated version of this system. Far from being the straightforward cascade containing one substrate [angiotensinogen], two peptides, [angiotensin (ANG) I, ANG II], two enzymes [renin, angiotensin-converting enzyme (ACE)] and one receptor (AT1), the RAS currently includes nearly a dozen of ANG fragments, some active and some inactive, more than two dozen peptidases, and at least six different receptors. Moreover, the RAS now consists of several axes upstream and downstream of the classical cascade. While sometimes, these newcomers are considered to be "missing links," more often they are viewed with skepticism. In addition, it is now well accepted that local RASs are present in most organs and tissues, including but not limited to the heart, kidney, vasculature, adipose tissue, pancreas, and brain, and they are involved in the local regulation of these tissues.Since its first description by Ganten et al. (3), in the early 1970s, the brain RAS has been the subject of controversy and debate. Is ANG II generated in the brain or does it travel from the periphery? Is ANG III the real ligand for the AT1 receptor in the CNS? Is Mas the receptor for ANG (1-7)? Is there a non-AT1, non-AT2 receptor? What is the binding site for ANG IV? Although some of these questions have been answered, for example, it is now well accepted that ANG II in the CNS can be generated locally, and it also can enter the brain via the circumventricular organs, other claims still spark debates.Probably the oldest controversy for the brain RAS concerns the presence of renin in the CNS. Because renin levels in the brain are usually low and likely not homogenous throughout the various nuclei, they have been difficult to assess. As a consequence, over the years, different theories have emerged, generally involving alternate pathways for the synthesis of ANG II. Accordingly, evidence has shown that the octapeptide could be produced via tonin, chymase, cathepsins, and other peptidases (see Ref. 11 for a full list). One of the latest possibilities for a renin-independent synthesis of ANG II involves the recently discovered ANG (1-12) peptide (12), which could eventually be transformed successively into ANG (1-10), then ANG II, through the action of ACE. However, as recently reviewed by Grobe et al. (4), genetic studies argue against renin-independent pathways, essentially because of the lack of phenotype in transgenic animals overexpressing angiotensinogen in the brain and support the presence of this enzyme in the CNS (1, 7). In addition, evidence has shown the existence of a nonsecreted intracellular form of the enzyme, renin-b, which is functional in the brain of rodents and humans (5).A new piece of the puzzle is presented in this issue (2) by Dr. Genevieve Nguyen's group. Here, the authors show evidence of the (pro)renin receptor [(P)RR] in the CNS. The (P)RR was discovered (8) and cloned from the X chromosome (9) by the Nguyen group. It is known to bind both renin and the "inactive" prorenin, resulting in increased activity of both enzymes, thus leading to enhanced formation of ANG I (Fig. 1). Interestingly, binding of the receptor also leads to the activation of ANG II-independent intracellular signaling pathways, ultimately leading to the expression of profibrotic genes, such as TGF-β, PAI-1, and others.Although the presence of the (P)RR was previously identified by this group in the brain (8) and by others in primary neurons (10), this is the first time, almost 15 years after its discovery, that the localization of the receptor is being mapped throughout the brain. Importantly, in this paper, Contrepas et al. (2), using in situ hybridization, show the presence of the (P)RR mRNA in various brain regions, some of them, like the subfornical organ (SFO), paraventricular nucleus, the supraoptic nucleus, the nucleus of the tractus solitarius (NTS), or the rostral ventrolateral medulla, being famous for their involvement in the central regulation of cardiovascular function and volume homeostasis. Of particular interest are the data showing that the (P)RR mRNA was highly expressed in the SFO and the NTS. Indeed, these two regions are very much involved in the fine-tuning of blood pressure (BP) regulation by being an "open window" to the periphery, and thus, sensitive to blood-borne RAS components, for the SFO, and by receiving information on the BP status, via the baroreceptor reflex afferents, for the NTS. Therefore, the presence of the (P)RR in these important nuclei suggests that it may play a role in the central regulation of BP, which opens new avenues in this field.The (P)RR in the brain, like other components of the RAS, is involved in additional functions, beyond the regulation of BP. Indeed, while ACE is required to maintain fertility and ACE2 serves as a receptor for the SARS coronavirus (6), mutation of the (P)RR is associated with X-linked mental retardation and epilepsy, and thus, (P)RR seems to be important for brain development and cognition. Therefore, another major finding by Contrepas et al. (2) is that the mutated version of the (P)RR, responsible for the mental retardation, while still capable of binding renin and forming dimers with the native receptor, affects the trafficking of this receptor to the neurite tips in cultured neurons. Moreover, for these mutated homodimers, the ANG II-independent signaling pathway was impaired, supporting the idea that the mutated receptor may act as a dominant negative and suggesting that ERK signaling plays an important role in neuronal differentiation. However, with one controversy almost resolved, another is coming, and several questions already need to be answered. For example, is the trafficking of the (P)RR to the neurite tips, part of a mechanism that would allow ANG II formation near the synaptic cleft? We previously mentioned that renin levels are assumed to be low in the brain, on the other hand, prorenin levels have been shown, in the plasma, to be 10 to 100 times higher than renin. Is the same true in the brain? Could prorenin, or another form of renin (4), be more relevant as enzymes in the brain or could its interaction with the (P)RR be the key to increased renin activity in the CNS? Also, Raizada's group (10) previously showed that the (P)RR, via a non-AT1-mediated pathway involving MAP kinases, was able to inhibit neuronal activity in vitro. This is rather unexpected since activation of the RAS is usually associated with neuronal excitation, and it has potentially interesting consequences. Indeed, upon confirmation in vivo, and assuming that this particular pathway could be selectively activated, this would confer on (P)RR some therapeutic properties, for example, during neurogenic hypertension when the overactivity of the RAS needs to be subdued. Obviously, these questions are only the tip of the iceberg, and many more are likely to emerge.In conclusion, the present study by Contrepas et al. (2) provides a major advancement of our knowledge of the function of the (P)RR in the brain in mental retardation and potentially the regulation of cardiovascular function. Although these data do not necessarily show that renin is generated in the CNS, they definitely support the fact that renin is playing major roles in the brain. Fig. 1.ANG II-dependent and independent pathways for renin signaling. Both renin and prorenin can bind the dimerized (pro)renin receptor [(P)RR], leading to the activation of different signaling pathways. Binding of prorenin to the receptor results in either direct activation of downstream MAP kinases signaling, or in the nonproteolytic activation of prorenin, facilitating the activation of ERK signaling cascades that can also be triggered by renin binding. Activation of these signaling cascades results in actin polymerization and the expression for profibrotic genes, leading to TGF-β, PAI-1, collagen-I, and fibronection synthesis. Binding of renin to the (P)RR also activates an ANG II-dependent pathway leading to the formation of ANG II and the activation of the AT1 receptor. Activation of both pathways ultimately leads to end-organ damage. Abbreviations: TGF-β, transforming growth factor β; PAI-1, plasminogen-activator inhibitor-1.Download figureDownload PowerPointThis work was supported by a grant from the National Institutes of Health Heart Lung and Blood Institute (HL-093178) to E. Lazartigues.REFERENCES1 Allen AM, O'Callaghan EL, Hazelwood L, Germain S, Castrop H, Schnermann J, Bassi JK. Distribution of cells expressing human renin-promoter activity in the brain of a transgenic mouse. Brain Res 1243: 78–85, 2008.Crossref | PubMed | ISI | Google Scholar2 Contrepas A, Walker J, Koulakoff A, Franek KJ, Qadri F, Giaume C, Corvol P, Schwartz CE, Nguyen G. A role of the (pro)renin receptor in neuronal cell differentiation. Am J Physiol Regul Integr Comp Physiol (May 27, 2009). doi:10.1152/ajpregu.90832.2008.Link | ISI | Google Scholar3 Ganten D, Minnich JL, Grenger P, Hayduk K, Brecht HM, Barbeau A, Boucher R, Genest J. Angiotensin-forming enzyme in brain tissue. Science 173: 64–65, 1971.Crossref | PubMed | ISI | Google Scholar4 Grobe JL, Xu D, Sigmund CD. An intracellular renin-angiotensin system in neurons: fact, hypothesis, or fantasy. Physiology 23: 187–193, 2008.Link | ISI | Google Scholar5 Lavoie JL, Liu X, Bianco RA, Beltz TG, Johnson AK, Sigmund CD. Evidence supporting a functional role for intracellular renin in the brain. Hypertension 47: 461–466, 2006.Crossref | PubMed | ISI | Google Scholar6 Lazartigues E, Feng Y, Lavoie JL. The two fACEs of the tissue renin-angiotensin systems: implication in cardiovascular diseases. Curr Pharm Des 13: 1231–1245, 2007.Crossref | PubMed | ISI | Google Scholar7 Morimoto S, Cassell MD, Sigmund CD. The brain renin-angiotensin system in transgenic mice carrying a highly regulated human renin transgene. Circ Res 90: 80–86, 2002.Crossref | PubMed | ISI | Google Scholar8 Nguyen G, Delarue F, Berrou G, Rondeau E, Sraer JD. Specific receptor binding of renin on human mesangial cells in culture increases plasminogen activator inhibitor-1 antigen. Kidney Int 50: 1897–1903, 1996.Crossref | PubMed | ISI | Google Scholar9 Nguyen G, Delarue F, Burckle C, Bouzhir L, Giller T, Sraer JD. Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109: 1417–1427, 2002.Crossref | PubMed | ISI | Google Scholar10 Shan Z, Cuadra AE, Sumners C, Raizada MK. Characterization of a functional (pro)renin receptor in rat brain neurons. Exp Physiol 93: 701–708, 2008.Crossref | PubMed | ISI | Google Scholar11 Speth R, Karamyan V. The significance of brain aminopeptidases in the regulation of the actions of angiotensin peptides in the brain. Heart Fail Rev 13: 299–309, 2008.Crossref | PubMed | ISI | Google Scholar12 Trask AJ, Jessup JA, Chappell MC, Ferrario CM. Angiotensin-(1–12) is an alternate substrate for angiotensin peptide production in the heart. Am J Physiol Heart Circ Physiol 294: H2242–H2247, 2008.Link | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: E. Lazartigues, Louisiana State Univ. Health Sciences Center, School of Medicine, Dept. of Pharmacology and Experimental Therapeutics, 1901 Perdido St., P7-1, New Orleans, LA 70112 (e-mail address: [email protected]) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationCited ByRole of the Angiotensin Pathway and its Target Therapy in Epilepsy Management8 February 2019 | International Journal of Molecular Sciences, Vol. 20, No. 3Many Faces of Renin-angiotensin System - Focus on EyeThe Open Ophthalmology Journal, Vol. 11, No. 1Ocular renin-angiotensin system with special reference in the anterior part of the eyeWorld Journal of Ophthalmology, Vol. 5, No. 3Development of Local RAS in Cardiovascular/Body Fluid Regulatory Systems and Hypertension in Fetal Origins4 September 2013The effects of para-chloromercuribenzoic acid and different oxidative and sulfhydryl agents on a novel, non-AT1, non-AT2 angiotensin binding site identified as neurolysinRegulatory Peptides, Vol. 184Nucleus of the Solitary Tract (Pro)Renin Receptor-Mediated Antihypertensive Effect Involves Nuclear Factor-κB-Cytokine Signaling in the Spontaneously Hypertensive RatHypertension, Vol. 61, No. 3Three key proteases – angiotensin-I-converting enzyme (ACE), ACE2 and renin – within and beyond the renin-angiotensin systemArchives of Cardiovascular Diseases, Vol. 105, No. 6-7Association of the Novel Non-AT 1 , Non-AT 2 Angiotensin Binding Site with Neuronal Cell Death22 September 2010 | Journal of Pharmacology and Experimental Therapeutics, Vol. 335, No. 3Involvement of the Brain (Pro)renin Receptor in Cardiovascular HomeostasisCirculation Research, Vol. 107, No. 7 More from this issue > Volume 297Issue 2August 2009Pages R248-R249 Copyright & PermissionsCopyright © 2009 the American Physiological Societyhttps://doi.org/10.1152/ajpregu.00287.2009PubMed19494175History Published online 1 August 2009 Published in print 1 August 2009 Metrics